Sudden unexpected death in epilepsy (SUDEP) is a devastating complication of epilepsy associated with generalized seizures. Seizure-induced respiratory and cardiac depression are proposed to be key mechanisms underlying SUDEP, but effective treatments are not currently available, partly due to lack of animal models that resemble human SUDEP. Recently, it has been reported that two substrains of DBA (DBA/1 and DBA/2) mice exhibit respiratory arrest, leading to cardiac arrest after generalized convulsive seizures, as has been observed in humans. Interestingly, systematic administration of a drug that enhances synaptic serotonin (5-HT) levels significantly reduced respiratory arrest evoked by generalized seizures in DBA mice, suggesting that 5-HT neurotransmission may play an important role in SUDEP. A recent retrospective clinical report indicates that seizure-induced respiratory depression is reduced in patients taking similar 5-HT agents. However, the neuronal network sites at which 5-HT may act to reduce seizure-induced respiratory arrest are currently unknown. We hypothesize that insufficient 5-HT neurotransmission in medullary respiratory center causes respiratory arrest evoked by generalized seizures in DBA/1 mice. This hypothesis is based on the following observations. First, medullary respiratory center has a well-established role in respiration, and 5-HT is a key modulator that regulates respiratory rhythm. Second, medullary brain lesions lead to sudden unexpected death in otherwise healthy humans. Third, deficits of 5-HT neurotransmission in medulla play a causative role in sudden infant death syndrome, a disorder thought to share similar pathophysiology with SUDEP. Finally, it has been shown that several subtypes of 5-HT receptors are abnormal in the brainstem (containing medullary respiratory center) of a substrain of DBA mice. We will test this hypothesis in DBA/1 mice because DBA/1 mice display susceptibility to respiratory arrest for several weeks more than DBA/2 mice (7 days). The specific aims of our proposal are to: 1) determine the effect of enhancing 5-HT neurotransmission in brainstem on respiratory arrest induced by generalized seizures in DBA/1 mice, and 2) determine whether and which 5-HT receptors in the pre-Botzinger complex of medullary respiratory center are involved in seizure-evoked respiratory arrest. Successful implementation of the proposed studies will not only shed important light on the mechanisms of SUDEP but also provide useful information on treatments for this devastating epileptic event. PUBLIC HEALTH RELEVANCE: Sudden unexpected death in epilepsy (SUDEP) is the major cause of death related to epilepsy. The pathophysiology of SUDEP is poorly understood, and there is a lacking in therapeutic and preventive treatments for this disorder. The goal of this research is to elucidate the neural circuit mechanisms of SUDEP to facilitate the development of effective treatment.